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Clinically amyopathic dermatomyositis (CADM) patients frequently develop refractory interstitial lung disease (ILD), with a poor prognosis. We aimed to verify the efficacy and safety of plasma exchange (PE) treatment for ILD in CADM.A retrospective case-control study was conducted to compare clinical outcomes with and without PE treatment in CADM-ILD patients refractory to combination therapy of high-dose glucocorticoids, calcineurin inhibitors, and cyclophosphamide. Among 19 enrolled patients, 11 were further treated with PE. We compared survival rates and other clinical characteristics. PE consisted of either fresh-frozen plasma or albumin as a replacement solution.Basal clinical characteristics at diagnosis, including age, gender, serum ferritin, Krebs von den Lungen-6 (KL-6), C-reactive protein, and respiratory function tests, did not differ between the two groups. The survival rate for treatment with PE was higher than for treatment without PE (91% and 50%, respectively, p 0.05). Among PE-treated patients, anti-melanoma differentiation-associated gene-5 (anti-MDA-5) antibody titre, ferritin, and KL-6 as serological activity markers were sustainably reduced only after initiating PE. Therapeutic intervention with PE reduced the frequency of exacerbation of ILD requiring methylprednisolone pulse therapy. The occurrence of bacterial, fungal, and cytomegalovirus infection did not differ between the groups with and without PE, and adverse events associated with PE resolved with appropriate intervention.Combination therapy with PE was associated with an improved survival rate, and may be effective for the management of refractory ILD in CADM patients. A personalized therapeutic strategy including PE could be introduced for fatal rapidly progressive ILD.

Soil moisture is a key factor for mercury (Hg) emission from soil. Despite its significance for Hg emissions, the effect of soil moisture on Hg flux and fractions has not been thoroughly investigated. The objective of this study was to elucidate the influences of soil moisture and temperature on Hg fluxes from soils and Hg fractions. A kinetic study was performed to measure Hg emission fluxes of six soil samples under different temperature (T) (15 °C, 20 °C, 25 °C, 30 °C, and 35 °C) and moisture conditions (0%, 10%, and 20% added water). The results showed that the Hg fluxes increased with increases in T and soil moisture. A linear correlation was found between ln (Hg emission flux) and 1/T for the six soil samples at different moisture contents (R

BackgroundIdiopathic inflammatory myopathy (IIM) is associated with a high prevalence of malignancy, in which anti-transcriptional intermediary factor 1-γ(TIF1-γ) antibody is at a high risk of malignancy compared to the other myositis-specific antibodies, including anti-aminoacyl-tRNA synthetase (ARS), melanoma differentiation-associated gene 5 (MDA5), and Mi-2 antibody [1]. Although some subgroups of IIM have a high risk of malignancy up to 10 years after diagnosis [2], long-term relationships between malignancy and each antibody are not elucidated so far.ObjectivesTo clarify the risk of malignancy in IIM in each antibody type with standard incidence ratios (SIR) of malignancy and the long-term occurrence of malignancy.MethodsFrom our IIM cohort at the University of Tokyo hospital, we enrolled patients who fulfilled with Bohan and Peter criteria for dermatomyositis/polymyositis or 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for IIMs and with positivity for anti-ARS, MDA5, Mi-2, or TIF1-γ antibody. We retrospectively collected the data and calculated SIRs by using the database of Cancer Statistics, Cancer Information Service, National Cancer Center, Japan. Fisher exact test and Wilcoxon test were used to compare the clinical features in each group. Cumulative incidence of cancer occurrence was estimated by Kaplan-Meier methods, and Log-rank test was used to compare the cancer-free survival.ResultsThe study included 111 patients, including 16 patients being diagnosed with a malignancy within a three-year before and after the occurrence of IIM. Patients with malignancy were significantly older age at the onset of IIM (median age (interquartile range) 67.5 (62.3-70.8) vs. 52.0 (41.5-61.5). pFigure 1.Comparison of malignancy rate of idiopathic inflammatory myopathy with anti-ARS, and TIF1-γ antibodies in 10 years.Table 1.Standard incident ratio (SIR) of malignancy in idiopathic inflammatory myopathy according to myositis-specific antibodies.Total (Person-years)ObservedExpectedSIR (95% CI)Anti-ARS antibody51083.622.21 (1.03-4.55)Anti-MDA5 antibody21031.591.89 (0.49-6.02)Anti-Mi-2 antibody5610.362.75 (0.14-17.84)Anti-TIF1-γ antibody3940.2714.73 (4.72-40.50)Total815165.842.74 (1.62-4.56)ConclusionIIM patients with anti-TIF1-γ antibody and with anti-ARS antibody had a higher prevalence of malignancy than the general population. In addition, anti-TIF1-γ antibody are more associated with malignancy rather than anti-ARS antibody in 10 years as well. Malignancy associated with anti-TIF1-γ positive IIM occurred exclusively within the one year before and after the IIM diagnosis, and cancer should be particularly investigated at the IIM diagnosis.References[1]DeWane ME, Waldman R, Lu J. Dermatomyositis: Clinical features and pathogenesis. J Am Acad Dermatol. 2020;82:267-281.[2]Lundberg IE, Fujimoto M, Vencovsky J, Aggarwal R, Holmqvist M, Christopher-Stine L, Mammen AL, Miller FW. Idiopathic inflammatory myopathies. Nat Rev Dis Primers. 2021;7:86.Characters from table content including title and footnotes: 3299Disclosure of InterestsShinji Izuka: None declared, Toshihiko Komai Speakers bureau: Tanabe Mitsubishi, Kissei, Pfizer, Amgen GlaxoSmithKline and Chugai., Grant/research support from: GlaxoSmithKline., Hirofumi Shoda Speakers bureau: Pfizer, Bristol-Myers Squibb, Eli Lilly, Sanofi, AbbVie, GlaxoSmithKline, Gilead, Boehringer Ingelheim, Jansen, Novartis, Chugai, Takeda, Astellas, Eisai, Asahi Kasei and Daiichi-Sankyo., Grant/research support from: Novartis, Keishi Fujio Speakers bureau: Tanabe Mitsubishi, Bristol-Myers Squibb, Eli Lilly, Chugai, Jansen, Pfizer, Ono, AbbVie, Ayumi, Astellas, Sanofi, Novartis, Daiichi Sankyo, Eisai, Asahi Kasei and AstraZeneca., Grant/research support from: Tanabe Mitsubishi, Bristol-Myers Squibb, Eli Lilly, Chugai, Eisai, Tsumura and Asahi Kasei.

It is necessary for patients with implanted medical devices to have surgery in order to change devices whose battery cells have run out. We have suggested changing the battery into a secondary rechargeable one with contactless energy transmission, but it has been difficult to transmit electrical energy without increasing the eddy loss caused by the metal case of the device. We designed a rechargeable cardiac pacemaker with contactless electrical energy transmission and confirmed that it has a secondary power transmission efficiency of 26-40% at 0.4 W. However, an implantable cardioverter defibrillator (ICD) needs a larger volumetric battery than a cardiac pacemaker. It is necessary to transmit a large amount of power without increasing the eddy current loss, and it is important to estimate the eddy loss caused by the metal case.

A new species of crangonid shrimp, Philocheras triangulus sp. nov., is described and illustrated. Two specimens were trawled from a coral sand bottom off West Alligator Head, Kakadu National Park, Northern Territory, Australia, at a depth of 7.3 metres in 2004. The possession of a single lateral tooth on the antennal scale aligns the new species to the seven known species of the genus also having this feature, but the triangular rostrum and the lack of a distinct mid-dorsal carina on the third and fourth pleonal somites immediately distinguish the new species from its congeners. The new species is the ninth Philocheras species known from Australia. A key to all nine species is given.

An analysis method for evaluating a polycrystal structure under a surface using x-ray diffraction at small glancing angle incidence was studied. Intensities of the diffracted x-rays on a polycrystalline iron surface were measured at various incidence angles, and the dependency of the incidence angles was investigated by analysing the intensity of x-ray propagation in surface layer materials characterized by a complex refractive index that changes continuously with depth. The dependence of the diffracted x-ray intensities on the glancing angle was analysed and the depth profile of the polycrystalline layers of oxidized iron was evaluated to an accuracy of the order of nanometres. Copyright © 2005 John Wiley & Sons, Ltd.

The Us3 kinase is part of the antiapoptotic arsenal that salvages herpes simplex virus (HSV)-1-infected cells from damage caused by different stimuli. We demonstrate that Us3 protects HSV-1-infected cells from lysis by MHC class I-restricted CD8T cells without affecting antigen presentation. Expression of Us3 was associated with inhibition of caspase activation and reduced cleavage of the proapoptotic protein Bid. Recombinant granzyme B (GrB) failed to cleave Bid in cytosolic extracts from Us3 positive cells, while recombinant Bid served as substrate for Us3 phosphorylation, suggesting that modification of Bid by Us3 blocks its processing by GrB. Our data illustrate a new strategy of viral escape, where modification of a cellular proapoptotic substrate may prevent lysis of the infected cells without affecting other T-cell functions.

We studied photoluminescence of Er in strained Si on a SiGe layer (Si:Er:O/SiGe) and unstrained Si on a Si layer (Si:Er:O/Si) grown by molecular beam epitaxy. Er-related photoluminescence was observed in both Si:Er:O/SiGe and Si:Er:O/Si samples. The peak intensity of Si:Er:O/SiGe at 1.54 μm was higher than that of Si:Er:O/Si. Moreover, the spectrum of strained Si (Si:Er:O/SiGe) was much broader than that of unstrained Si (Si:Er:O/Si). These differences between Si:Er:O/SiGe and Si:Er:O/Si suggest that the optical activation of Er can be enhanced by the presence of strain.

Five species of the hermit crab genus Paguristes Dana, 1851, initially reported by Ortmann (1892) from Japan, are revised based on the materials reported by Ortmann (1892), Doflein (1902), Balss (1913) and Miyake (1978), and on newly collected specimens. The specific status of P. palythophilus Ortmann, 1892, is clarified, and a species confused with P. palythophilus is described as new, P. albimaculatus. It has been revealed that P. kagoshimensis Ortmann, 1892, is actually a junior subjective synonym of P. digitalis Stimpson, 1858. The species heretofore assigned to P. kagoshimensis is described as new, P. versus. It has been confirmed that Paguristes acanthomerus Ortmann, 1892, is a valid species and that P. barbatus sensu Ortmann, 1892, is the same species as P. ortmanni Miyake, 1978. Further, a new species, P. doederleini, is described for P. setosus sensu Ortmann, 1892. It is also shown that a part of the group of specimens identified as Paguristes puniceus by Miyake (1978) is referable to P. doederle...

Glacial Lake Lind developed in the pre–late Wisconsinan St. Croix River valley, Minnesota and Wisconsin, and lasted more than 1000 yr during the retreat of the Superior lobe at the end of the Wisconsinan glaciation. Lake Lind sediment consists primarily of red varved silt and clay, but also includes mud-flow deposits, nearshore silt (penecontemporaneously deformed in places), nearshore rippled sand, and deltaic sand. Lake Lind varved red clay is not part of glacial Lake Grantsburg, as suggested by earlier authors, because the red varves are separated from overlying glacial Lake Grantsburg silt and clay by a unit of deltaic and fluvial sand. Furthermore, varve correlations indicate that the base of the red varves is younger to the north, showing that the basin expanded as the Superior lobe retreated and was not a lake basin dammed to the southwest by the advancing Grantsburg sublobe. Varve correlations indicate that the Superior lobe retreated at a rate of about 200 m/yr. Uniform winter-clay thickness throughout most of the varve couplets suggests thermal stratification in the lake with clay trapped in the epilimnion; some clay would exit the lake at the outlet prior to winter freeze. Zones of thicker winter-clay layers, in places associated with mud-flow layers, indicate outlet incision, lake-level fall, and shoreline erosion and resuspension of lake clay. The most likely outlet for glacial Lake Lind was in the southwest part of the lake near the present site of Minneapolis, Minnesota. Nearshore sediment indicates that the lake level of glacial Lake Lind was around 280 m. The elevation of the base of the Lake Lind sediments indicates water depth was 20 to 55 m. Evidence in the southern part of the lake basin suggests that the Superior lobe readvanced at least once during the early stages of glacial Lake Lind. Lake Lind ended not by drainage but by being filled in by prograding deltas and outwash plains composed of sand derived from the retreating Superior lobe. It was upon this fluvial surface that the Grantsburg sublobe advanced, depositing till and forming glacial Lake Grantsburg.

New and simple human immunodeficiency virus type 1 (HIV-1) protease expression methods in Escherichia coli were developed using the T7 phage promoter system. In order to suppress leaky HIV-1 protease expression under the control of the T7 polymerase, two new methods were tested. One involved the introduction of supplementary T7 promoter regions into host cells [E. coli BL-21 (DE3)] containing the HIV-1 protease gene under the control of the T7 promoter. It was expected that the supplementary T7 promoter regions would compete with the HIV-1 protease expression vector for the T7 polymerase binding. The other involved the infection of late-log-phase cultures of E. coli JM109 harboring the same HIV-1 protease expression vector with the M13 phage expressing T7 polymerase. Both methods were effective, and transformants with the mature HIV-1 protease expression vector showed ten times higher HIV-1 protease activity than activities obtained with the autoprocessing vector. The expression systems described here are convenient and are also easily applicable for the expression of other proteins toxic for E. coli.

To examine whether the relatively selective inhibition of hepatic cholesterol synthesis by the hydrophilic 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pravastatin in vivo may be due to the existence of a specific uptake mechanism in the liver, the uptake by isolated rat hepatocytes was investigated. The uptake was composed of a saturable component [Michaelis constant (Km) 29 microM, maximal uptake rate 546 pmol.min-1.mg-1] and nonspecific diffusion (nonspecific uptake clearance 1.6 microliters.min-1.mg-1), inhibited by hypothermia, metabolic inhibitors, sulfhydryl-modifying reagents, and inhibitor of anion exchanger, whereas replacement of Na+ by choline+ or Cl- by gluconate- did not alter the uptake. Competitive inhibition was observed by a more highly lipophilic HMG-CoA reductase inhibitor simvastatin (open acid form), dibromosulfophthalein, cholate, and taurocholate. Pravastatin inhibited Na(+)-independent taurocholate uptake with an inhibition constant comparable with the Km value of pravastatin itself. Furthermore, the hepatic permeability clearance in vivo obtained with intact rats was comparable with that in vitro, indicating that the carrier-mediated active transport system we demonstrated in vitro is responsible for the hepatic uptake in vivo. These findings demonstrated that the hepatic uptake of pravastatin occurs via a carrier-mediated active transport mechanism utilizing the so-called multispecific anion transporter, which is common with the Na(+)-independent bile acid uptake system, and that this is one of the mechanisms for its selective inhibition of hepatic cholesterol synthesis in vivo.

The complete larval development of Pandalopis japonica Balss, 1914, is described and illustrated in detail based on laboratory reared material. There are three larval stages, each showing advanced features. The first and third stages are referable to zoea and megalopa as strictly defined by Williamson (1969), but the second stage cannot be referred to any phase. The fourth and following stages are juveniles. The larval characteristics are compared with those of described congeners. The larvae of P. japonica are unique even among known pandalids' larvae in that they lack pereopodal exopods. The phylogenetic significance of larval morphology as it relates to developmental pattern is also discussed.

Komai, T., Yamasaki, I., Kobayashi, S., Yamamoto, T., Watanabe, S. (2006): Eriocheir ogasawaraensis Komai, a new species of mitten crab (Crustacea: Decapoda: Brachyura: Varunidae) from the Ogasawara Islands, Japan, with notes on the systematics of Eriocheir De Haan, 1835. Zootaxa 1168: 1-20, DOI: 10.5281/zenodo.2645512, {"references":["Dai, A., Yang, S., Song, Y., & Chen, G. (1986) Crabs of the Chinese Seas. China Ocean Press, Beijing. 642 pp. [in Chinese]","Gao, T. & Watanabe, S. (1998) Genetic relationship between the Japanese mitten crab, Eriocheir japonica and the Chinese mitten crab, Eriocheir sinensis. Aquaculture, 46, 171-176. [in Japa- nese, with English abstract]","Guo, J.Y., Ng, N.K., Dai, A.-Y., & Ng, P.K.L. (1997) The taxonomy of three commercially important species of mitten crabs of the genus Eriocheir De Haan, 1835) (Crustacea: Decapoda: Brachyura: Grapsidae). Raffles Bulletin of Zoology, 45, 445-476.","Kobayashi, S. (2005) Survey on the enormous mitten crabs in Bonin Islands. Cancer, 14, 17-22. [in Japanese]","Li, S.-F., Shen, Q., & Xu, Z.-X. (1993) Morphometric and biochemical genetic variation of the mitten crab, in southern Chiba. Aquaculture, 111, 103-115.","Lu, R.-H., Qiu, T., Xiang, C.-M., Xie, H., & Zhang, J. (2000) RAPD and AFLP techniques for the analysis of genetic relationships in two genera of Decapoda. Crustaceana, 73, 1027-1036.","Miyake, S. (1970) Crustacea. In: [Modern Biology]. Vol. 1, Invertebrates A. Nakayama-shoten, pp. 256-296. [in Japanese]","Miyake, S. (1983) Japanese Crustacean Decapods and Stomatopods in Color, Vol. II. Hoikusya, Osaka, 277 pp., 64 pls.","Montu, M., Anger, K. and de Bakker, C. (1996) Larval development of the Chinese mitten crab Eriocheir sinensis H. Milne Edwards (Decapoda: Grapsidae) reared in the laboratory. Helgolander Meeresunters, 50, 223-252.","Muraoka, K. (1998) Catalogue of the Brachyuran and Anomuran Crabs Donated by Prof. Dr. Tune Sakai to the Kanagawa Prefectural Museum. Catalogue of the Collection in the Kanagawa Prefectural Museum of Natural History 11. Kanagawa Prefectural Museum of Natural History, Odawara, 67 pp., 16 pls. [in Japanese]","Ng, N.K., Guo, J., & Ng, P.K.L. (1999) Generic affinities of Eriocheir leptognathus and E. formosa with description of a new genus (Brachyura: Grapsidae: Varuninae). Journal of Crustacean Biology, 19, 154-170.","Sakai, T. (1939) Brachygnatha, Brachyurhyncha. Studies on the crabs of Japan IV. Yokendo, Tokyo, 365-741 pp.","Sakai, T. (1976) Crabs of Japan and the Adjacent Seas. Kodansha, Tokyo, xxix + 773 pp. (English text), 461 pp. [Japanese text], 251 pls.","Sakai, T. (1983) Descriptions of new genera and species of Japanese crabs, together with systematically and biogeographically interesting species. Researches on Crustacea, 12, 3-23.","Stimpson, W. (1858) Prodromus descriptionis animalium evertebratorum, quae in Expeditione ad Oceanum Pacificum Septentrionalem, a Republica Federata missam Cadwaladaro Ringgold et Johanne Rodgers ducibus, observavit et descripsit, Pars V. Crustacea Ocypodoidea. Proceedings of the Academy of Natural Sciences of Philadelphia, 10, 93-111.","Stimpson, W. (1907) Report on the Crustacea (Brachyura and Anomura) collected by the Pacific Exploring Expedition, 1853-1856. Smithsonian Miscellaneous Collection, 49, 1-240, pls. 1-26.","Takeda, M., & Miyake, S. (1976) Crabs of the Ogasawara Islands. 1. List of the known species. Researches on Crustacea, 7, 101-115. [in Japanese]","Tang, B., Zhou, K., & Song, D. (2004) A neotype of Eriocheir recta (Crustacea, Decapoda). Acta Zootaxonomica Sinica, 29, 255-259. [in Chinese, with English abstract]","Tang, B., Zhou, K., Song, D., Yang, G., & Dai, A. (2003) Molecular systematics of the Asian mitten crabs, genus Eriocheir (Crustacea: Brachyura). Molecular Phylogenetics and Evolution, 29, 309-316.","Yamamoto, T. (2004) [Is Eriocheir mitten crab endemic species?]. i-Bo, 11, 16-17. [in Japanese]","Yamasaki, I., Yoshizaki, G., Yokota, M., Strussmann, C. A., & Watanabe, S. (in press) Mitochondrial DNA variation and population structure of the Japanese mitten crab, Eriocheir japonica. Fishery Science."]}

To evaluate an interaction between simvastatin and itraconazole in in vitro studies and to attempt a quantitative prediction of in vivo interaction in humans.The inhibitory effect of itraconazole on simvastatin metabolism was evaluated using human liver microsomes and the Ki values were calculated for the unbound drug in the reaction mixture. A physiologically-based pharmacokinetic model was used to predict the maximum in vivo drug-drug interaction.Itraconazole competitively inhibited the metabolism of simvastatin to M-1 and M-2 with Ki values in the nM range. The area under the curve (AUC) of simvastatin after concomitant dosing with itraconazole was predicted to increase ca. 84-101-fold compared with that without administration of itraconazole. Taking into consideration the fact that this method predicts the maximum interaction, this agrees well with the clinical observation of a 19-fold increase. A similar prediction, based on the Ki value without taking into account the drug adsorption to microsomes, led to an underevaluation of the interaction.It was demonstrated that the competitive inhibition of CYP3A4-mediated simvastatin metabolism by itraconazole is the main cause of the drug interaction and that a Ki value corrected for drug adsorption to microsomes is the key factor in quantitatively predicting the maximum in vivo drug interactions.

Taking into account the species and sex differences in drug interactions based on the inhibition of cytochrome P450 (P450)-mediated drug metabolism, we examined whether the interaction between simvastatin and itraconazole observed in humans could also occur in rats, the most commonly used animal species for pharmacokinetic studies. Itraconazole inhibited the in vitro metabolism of simvastatin in female rat liver microsomes, but not in male rat liver microsomes. Using anti-P450 antisera, the main P450 isozyme responsible for the metabolism of simvastatin was identified as CYP3A in female rats and CYP2C11 in male rats. Therefore, the sex difference in the inhibition of simvastatin metabolism by itraconazole seems to be caused by a difference in the P450 isozymes responsible for the metabolism of simvastatin in male and female rats and the different ability of itraconazole to inhibit CYP3A and CYP2C11. In addition, the effect of itraconazole on the pharmacokinetics of simvastatin in rats was also investigated. The area under the curve value of simvastatin was increased approximately 1.6-fold by the concomitant use of itraconazole (50 mg/kg) in female rats, whereas in male rats, itraconazole had no effect. In conclusion, it was found that the results obtained in male rats did not reflect the results in humans as far as the inhibition of simvastatin metabolism by itraconazole was concerned. The P450 isozymes involved in the metabolism of drugs should be taken into consideration when rats are used as a model animal for humans in the investigation of drug interactions.

HMG-CoA reductase inhibitors can be divided into two groups: those administered as the prodrug, i.e., the lactone form (e.g., simvastatin and lovastatin), and those administered in the active form, i.e., the acid form (e.g., pravastatin, fluvastatin, atorvastatin, and cerivastatin). In this study, the influence of the lactone and acid forms of various HMG-CoA reductase inhibitors on metabolism by CYP3A4, a major cytochrome P450 isoform in human liver, was investigated by determining the in vitro inhibition constant (K(i) value) using an antianxiety agent, mexazolam, as a probe substrate. In human liver microsomes, all the lactone forms tested inhibited the oxidative metabolism of mexazolam more strongly than did the acid forms, which have lower partition coefficient (logD(7.0)) values. In addition, the degree of inhibition of mexazolam metabolism tended to increase with an increasing logD(7.0) value of the HMG-CoA reductase inhibitors among the lactone and acid forms. In particular, pravastatin (acid form), which has the lowest logD(7.0) value, failed to inhibit CYP3A4 activity. Taking account of the lipophilicity of the inhibitors, in conjunction with the CYP3A4-inhibitory activity, could be very useful in predicting drug interactions between substrates of CYP3A4 and HMG-CoA reductase inhibitors.

The mode of action of R-91650, an arylpiperazinyl fluoroquinolone, on feline immunodeficiency virus (FIV) replication inhibitory activity was investigated. R-91650 inhibited replication of FIV at non-cytotoxic concentration levels in both acutely infected peripheral blood mononuclear cells and chronically infected P-CrFK cells. The compound reduced the intracellular p24 concentration levels in P-CrFK cells in a dose-dependent manner. Northern blot analysis revealed that R-91650 selectively prevented the accumulation of FIV mRNA in P-CrFK cells. However, the compound did not inhibit FIV-long terminal repeat (LTR) promoter activity in the reporter gene expression analysis. These data suggest that R-91650 is a novel inhibitor of FIV replication that inhibits a certain step or steps following transcription initiation of the FIV-LTR promoter.

The pharmacokinetics of troglitazone (CAS 97322-87-7, CS-045), a new oral antidiabetic drug for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), were investigated in rats, mice and dogs following oral and intravenous administration of 14C-labeled troglitazone at doses of 5 mg/kg. The absorption rates, calculated from the AUC ratios of total radioactivity after oral and intravenous administration, or from the biliary excretion rate after intraduodenal administration in rats were both as high as 75%. High uptake by the liver, one of the pharmacological target organs, was demonstrated in both rats and mice. Furthermore, in the KK mouse, an obese NIDDM model animal, the radioactivity was incorporated selectively as troglitazone itself to muscle, the peripheral target organ. Troglitazone reversibly bound to serum albumin with a high ratio (99%). Troglitazone was mostly metabolized to the conjugates: sulfate (M 1) and glucuronide (M 2). The oxidized metabolite, a quinone-type metabolite (M 3), was found to be further metabolized to the sulfate (U 2). The biliary excretion rates of these conjugates were high in each animal, and the occurrence of enterohepatic circulation of the conjugates was also suggested. Sex differences in pharmacokinetics were observed in rats; i.e. females showed a higher plasma concentration of troglitazone, and a lower concentration of M 1, than males, and they excreted the sex-related metabolite, a hydroxylated M 1 (U 1), in the bile.

We have already demonstrated that the HMG-CoA reductase inhibitor, pravastatin is actively taken up by isolated rat hepatocytes via a multispecific anion transporter (Yamazaki et al., Am. J. Physiol. 264, G36-44, (1993)). We further attempted the quantitative evaluation of this uptake in different experimental systems.We have quantified the initial uptake of pravastatin by both primary cultured hepatocytes and by isolated perfused rat liver using the multiple indicator dilution (MID) method.The permeability surface area product for the influx (PSinf) of pravastatin evaluated in MID study was comparable with those reported previously in isolated rat hepatocytes and in vivo. Furthermore, the highly concentrative uptake (influx clearanceefflux clearance) of pravastatin was confirmed by kinetic analysis of the dilution curves obtained in the MID study. On the other hand, the uptake by primary cultured cells was significantly lower than that by isolated cells, and the ability of hepatocytes to take up pravastatin showed a decrease with time in culture (0-96 hr). The Vmax for uptake diminished with increasing time in culture, while no significant change was observed in both Km and nonspecific diffusion clearance.The MID method in isolated perfused liver which maintains the spatial and anatomical architecture can be used to quantitatively evaluate the initial uptake of pravastatin. Furthermore, the ability of hepatocytes to take up pravastatin is diminished in culture with time and this is caused by a decrease in Vmax.

Elimination of cryoprecipitable plasma components (cryogels) by cryofiltration from the circulating blood of patients with drug-resistant rheumatoid arthritis (RA) alleviates clinical symptoms including morning stiffness and arthralgia. The cryogels thus isolated from the blood were found to consist mainly of fibrinogen (Fbg) and fibronectin (FN). Analysis by immunoblotting with an anti-cellular FN monoclonal antibody revealed that cellular FN (cFN) co-existed with plasma FN (pFN) in the cryogels derived from the patients. Using an ELISA, we assessed cFN together with the total FN (pFN+cFN) in plasmas and cryogels derived from the patients. The cFN/total FN ratio was distinctly higher in the cryogels than in the plasmas, suggesting that cFN was more readily precipitated than pFN in association with Fbg under cold conditions.

To investigate the role of granulocytes and the effect of granulocytosis on malignancies, we studied the relationship between white blood cell and granulocyte (Gr) counts, and tumor size. As we have reported that cancer patients with high granulocyte (G/L) ratio have a poor clinical prognosis, normalization of the G/L ratio could contribute to improvement in their condition. Tumor bearing rabbits treated with the extracorporeal granulocytte depletion device showed a decrease in tumor size and no tumor necrosis. Tumor-bearing rabbits with no extracorporeal granulocyte depletion showed a remarkable tumor progression and an increase in Gr count. Depletion of granulocytes considerably improved the survival ratio of tumor-bearing animals. The device used in this study could be a potential treatment for malignant tumors.

Pravastatin sodium (pravastatin) is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and was found to be highly effective in animals and humans, in lowering the plasma cholesterol level by inhibiting cholesterol synthesis selectively in the liver. In the present study the disposition and metabolism of pravastatin was studied in rats, dogs and monkeys using [14C]-labelled compound. The extent of absorption was approximately 70% in rats and 50% in dogs. Tissue distribution examined by both whole-body autoradiography and radioactivity measurement demonstrated that the drug was selectively taken up by the liver, a target organ of the drug, and excreted via bile mainly in unchanged form. Since pravastatin excreted by the bile was reabsorbed, the enterohepatic circulation maintained the presence of unchanged pravastatin in the target organ. The profiles of metabolites were studied in various tissues and excreta and a metabolic pathway of pravastatin was proposed.

Modified spinal fusion curettes with two unusual features on the tip are described for anterior cervical procedures. The features are: 1) an elliptical, long sidewise ("brachycephalic") scoop at the tip and 2) a serration equipped on the distal scoop edge. These designs allow reliable manipulation and significant removal of the intervertebral space contents in the deep operative field under the microscope.

Modified spinal fusion curettes with two unusual features on the tip are described for anterior cervical procedures. The features are: 1) an elliptical, long sidewise ("brachycephalic") scoop at the tip and 2) a serration equipped on the distal scoop edge. These designs allow reliable manipulation and significant removal of the intervertebral space contents in the deep operative field under the microscope.

The electronic and magnetic properties of the ceramic superconductor YBa2 (Cu1-xFex)3O7-δ with x =0.010, 0.017, 0.033 and 0.067 have been studied microscopically by Mossbauer technique. We have shown that Fe's are substituted for both Cu 1 and Cu 2 sites. We have also shown that the samples with x >; 0.01 undergo a magnetic transition at low temperatures without destroying the superconductivity, and that the magnetic transition temperature TM increases with x. The coexistence of the superconductivity and the magnetic order is discussed, and it is argued that spin fluctuations of Cu are related to the superconductivity.

Local measurement of the mass-transfer rate and velocity gradient when an axisymmetric jet impinges on a flat plate was carried out using an electrochemical technique. Local measurement of the surface pressure on the flat plate was carried out separately using piezoelectric pressure transducers. The stagnation-point mass-transfer coefficient reaches a maximum when the flat plate is placed at 6 nozzle diameters from a convergent nozzle. It has been confirmed that the mass transfer to the flat plate for a high Schmidt number is greatly enhanced owing to the velocity-gradient disturbances in the wall region of the boundary layer, while the momentum transfer is insensitive to such disturbances. The relative intensity of the velocity-gradient fluctuations on the wall has an extremely large value at and near to the stagnation point, and decreases downstream, approaching a large constant value.These velocity-gradient disturbances are not due to the usual interaction of Reynolds stress with the shear stress of the mean flow, but are due to the interaction with the surface-pressure fluctuations converted from the velocity fluctuations of the oncoming jet.The three co-ordinate dimensions of large-scale eddies are calculated from the auto- and spatial correlations of the surface-pressure fluctuations. It is considered that such large-scale eddies play an important role in the production of a velocity-gradient disturbance in the wall region of the boundary layer from the velocity turbulence of the approaching jet.

An experimental investigation was done by the use of electrochemical technique in order to obtain the interrelation between the axial movement of Taylor vortices and the periodically varying rates of heat/mass transfer on the internal surface of the outer cylinder. When the Reynolds number of the axial flow is raised gradually at a fixed value of the Taylor number of the rotating flow, the regular sinusoidal variation of Sherwood numbers is distorted by the axial flow added, and then its mean value and amplitude are greatly reduced. The axial flow causes the damping effect not only on the initial formation of Taylor vortices but also on the heat/mass transfer mechanism involved in the momentum vortex boundary layer. It has been found that application of the heat-transfer data obtained for zero axial flow rate in order to design this type of heat exchanger with small, constant axial flow leads to dangerous 30–50% underestimation of the surface area of heat transfer in the experimental range.

The machanism of intestinal absorption of amino-β-lactam antibiotics was studied using 125I labelled cefatrizine of high radioactivity in rat by in situ ligated loop method and in vitro intestinal segment method. Iodocefatrizine (125I-CFT) retained the same antimicrobial activity and intestinal permeability as cefatrizine. 125I-CFT was taken up by the tissue against a concentration gradient. The tissue accumulation of 125I-CFT was highly temperature dependent and was inhibited by metabolic inhibitors. The rate of 125I-CFT uptake was decreased in the presence various amino-cephalosporins, amino-penicillins and dipeptides in the medium, but not affected by mono-carboxyl cephalosporins and amino acids. These results demonstrate that 125I-CFT is absorbed through the intestinal tissue by the carriermediated transport system. In addition, the usefulness of application of 125I-labelled compounds, which can be easily prepared with very high specific radioactivity, in the biochemical pharmacology studies was also exemplified.

Wear during dry sliding of steel against bronze has been investigated. The effects of time of sliding, load and velocity of sliding were assessed. A wear mechanism is postulated to explain the results under the conditions of test.

Cobalt-57-bleomycin is a clinically useful tumor-localizing agent, but attempts to label bleomycin (BLEO) with other radionuclides have been made because of the long physical half-life of 57Co. As an alternative labeling approach, we iodinated BLEO both directly on the imidazole ring and indirectly by reaction with N-succinimidyl 3-(4-hydroxy, 3-iodophenyl) propionate. Directly iodinated BLEO retained antibacterial activity, but in tumor-bearing rats it showed a lower tumor-to-blood ratio (2.3) at 2 hr than did 57Co-BLEO (11.8). The antibacterial activity of the indirectly labeled BLEO was markedly reduced and this material showed a tumor-to-blood ratio of 0.55 at 2 hr. The radioiodinated bleomycins are not suitable substitutes for 57Co-BLEO as tumor-imaging radiopharmaceuticals.

The chemically modified materials arising from natural tissue or organs sometimes show excellent blood-compatibility and can be utilized in reconstructive surgery. Hundreds of glutaraldehyde-treated human umbilical cord vessels (GA.UCV) have been implanted in humans as an artificial blood vessel and acetylated bovine pericardium (AC.PC) appears to be very promising as a material for the substitution of bladder tissue. (1–3). Both GA.UCV and AC.PC are well known to be composed of collagen, polysaccharide and lipid, and their surfaces are comparatively hydrophobic. In spite of the successful utilization of these materials in therapeutic reconstructive surgery, the characteristics and functional properties of these conjugated materials still remain to be clarified, mainly because of their complicated chemical and physical structures. An examination of model compounds simulating the GA.UCV or AC.PC surfaces chemically, should provide some understanding of this. (4–6). Accordingly, we prepared acylated chitins with various lengths of acyl groups in side chain hydroxy groups as model compounds simulating lipid polysaccharide conjugates and investigated their practical use as materials for blood contacting surfaces. (7). In this study, we have attempted to elucidate the relationship between the various types of acylated chitin and the thrombo-resistant properties and wetting characteristics of the respective materials.

14C-N-Ethylmaleimide-S-cysteinylglycine was used to investigate the role of dehydropeptidase-I in the metabolism of glutathione conjugates. The dipeptide was rapidly hydrolyzed to 14C-N-ethylmaleimide-S-cysteine in isolated rat renal cells, and subsequently acetylated to 14C-N-ethylmaleimide-S-N-acetylcysteine. Cilastatin, a specific inhibitor of dehydropeptidase-I, strongly inhibited the hydrolysis of the dipeptide by the isolated cells. In rat kidney homogenates, the marked inhibitory effect of cilastatin was also observed on the hydrolysis of cystinyl-bis-glycine and leukotriene D4, which are dipeptide intermediates in the biotransformation of oxidized glutathione and endogenous glutathione conjugate, respectively. In contrast, the inhibitory effect of bestatin, a potent inhibitor of aminopeptidase-M, was much smaller than that of cilastatin on the hydrolysis of these dipeptides by the renal cells and homogenates. These results suggest that dehydropeptidase-I plays a more important role in the metabolism of glutathione and its conjugates than aminopeptidase-M does.

Biodegradability of the poly(epsilon-benzyloxycarbonyl-L-lysine) membrane was tested for use as a biodegradable graft for the reconstruction of rabbit urinary bladder. Rabbit urinary bladder was exposed through a midline incision under general anesthesia and segmental resection with full thickness was done, with replacement by this synthetic membrane. The membrane was gradually reabsorbed, serving as a framework of support for regeneration of normal bladder tissues. Follow-up study at 1 year revealed no urinary tract complications, such as bladder stones or urinary tract infection. Also, no disturbance of renal function was demonstrated. Bladder capacity remained within normal limits and bladder functions were almost normal. These results indicate that biodegradable membrane may be well suited to this clinical use.

Traumatic hemorrhages in the basal ganglia were seen in five children. The CT findings and the characteristics of these injuries were discussed. All of children were injured in car accidents. They ranged in age from 3 to 13 years. The patients comprised 3 boys and 2 girls. On admission, case 1 was conscious and case 2 was in a stupor. Case 1 and 2 were mild cases in which spotty hematomas were seen in the ganglionic region. They recovered fully. Case 3-5 were severe cases in which massive hematomas were seen in the ganglionic region. On admission, their consciousness ranged from stupor to coma. We performed operations on two of them but their recoveries were unsatisfactory. Their results were as follows. One had residual hemiparesis and dysarthria, one experienced tetraparesis and dysarthria and the last went from coma to a vegetative state. Concerning the directions of the impacts, 4 were hit in the frontal region or face and the last one received blows on the occipital region. Skull fractures were seen in two cases. Mandibula and clavicula fractures were seen in the other two cases. Only one child had no fractures. We conclude that pediatric traumatic hemorrhages in the basal ganglia are induced by severe impact on the frontal or occipital regions. The size of hematomas in this injury is spotty or massive. The massive type has a poor prognosis. On the other hand, the spotty type's prognosis is good. We speculate that impact to the head causes a shear strain in the ganglionic region. At that time, vessels in the area are injured.